Propagation of meandering rotors surrounded by areas of high dominant frequency in persistent atrial fibrillation

Background: Identification of arrhythmogenic regions remains a challenge in persistent atrial fibrillation (persAF). Frequency and phase analysis allows identification of potential ablation targets. Objective: This study aimed to investigate the spatiotemporal association between dominant frequency (DF) and reentrant phase activation areas. Methods: A total of 8 persAF patients undergoing first-time catheter ablation procedure were enrolled. A noncontact array catheter was deployed into the left atrium (LA) and 2048 atrial fibrillation electrograms (AEGs) were acquired for 15 seconds following ventricular far-field cancellation. DF and phase singularity (PS) points were identified from the AEGs and tracked over consecutive frames. The spatiotemporal correlation of high DF areas and PS points was investigated, and the organization index at the core of high-DF areas was compared with that of their periphery. Results: The phase maps presented multiple simultaneous PS points that drift over the LA, with preferential locations. Regions displaying higher PS concentration showed a degree of colocalization with DF sites, with PS and DF regions being neighbors in 61.8% and with PS and DF regions overlapping in 36.8% of the time windows. Sites with highest DF showed a greater degree of organization at their core compared with their periphery. After ablation, the PS incidence reduced over the entire LA (36.2% ± 23.2%, P < .05), but especially at the pulmonary veins (78.6% ± 22.2%, P < .05). Conclusion: Multiple PS points drifting over the LA were identified with their clusters correlating spatially with the DF regions. After pulmonary vein isolation, the PS’s complexity was reduced, which supports the notion that PS sites represent areas of relevance to the atrial substrate

Are atrial fibrillation highest dominant frequency (HDF) areas the source of dominant excitation patterns? A left atrial panoramic view

Atrial fibrillation (AF) catheter ablation success depends on the possibility to accurately determine areas on the atrial endocardium at which AF activation originates. One way to determine if major AF activation pathways originate at identified source is through causality analysis. This work assessed to what extent left atrial highest dominant frequency (HDF) areas can be identified as sources of activation pathways in 10 male subjects suffering from persistent AF. Virtual electrograms were collected from 64 endocardial locations for at least 5 minutes. Frequency and causality were analyzed on 4 s signal segments Causality was assessed using the directed transfer function (DTF) algorithm, and AF activation sources were identified as endocardial locations of which the VEGM signal had high influence on other VEGM signals. Co-localization of high influence and HDF areas was evaluated for different area overlap and spectral organisation (OI) thresholds. Results show that, on average, good overlap only existed in 64.6% (± 8.8%) over all subject using the lowest threshold settings. Good overlap rates reduced with more conservative thresholds. This indicates that HDF areas might not always identify origins of main AF activation pathways

Dynamic behavior of rotors during human persistent atrial fibrillation as observed using non-contact mapping

Rotors have been related to atrial fibrillation (AF) maintenance. We analyzed the behavior of rotors in persistent AF (persAF) utilizing a novel non-contact methodology and compared this to real time dominant frequency (DF) analysis. 2048 noncontact virtual unipolar atrial electrograms (VEGMs) were collected simultaneously (EnSite Array, St. Jude Medical) from 10 persAF patients (duration: 34 ± 25 months) undergoing left atrial (LA) ablation. After QRST-removal, FFT was used to identify the global DF of the LA (range 4-10 Hz; 1 s time-window; 50 % overlap; highest DF (HDF) (DF -0.25 Hz); up to 20 s/patient). The organization index (OI) was measured and phase was found via Hilbert-transform. Phase singularities (PSs) were tracked and were categorized according to their lifespan into short (lifespan 100 ms). A total of 4578 PSs were tracked. 5.05 % (IQR: 2.75 ~ 30.25 %) of the tracked PSs were long-lived and were observed in 11 % (IQR: 2.75 ~ 17.5 %) of the windows. The windows with rotors showed significantly higher HDF (mean ± SD, 8.0 ± 0.43 Hz vs 7.71 ± 0.50 Hz, p<; 0.0001) and lower OI (0.76 ± 0.04 vs 0.79 ± 0.03, p<; 0.0001) when compared with the short-lived PSs windows. During persAF, the LA showed distinct behaviors as characterized by rotors. Often, no rotors were observed during sustained AF and, when present, the rotors continually switched between organized and disorganized behaviors. Long-lived rotors correlated with higher atrial rates. Our results suggest that rotors are not the sole perpetuating mechanism in persAF

Persistent atrial fibrillation hierarchical activation: from highest DF sites to wave fractionation at the boundaries

Preclinical studies showed a relationship between high dominant frequency areas (HDFA) and wave fractionation, but evidence in patient who atrial fibrillation (AF) persists for long-term periods (persAF) it is not well defined. This study aims to assess the spatiotemporal organization characteristics at HDFAs is persAF and its impact after per standard pulmonary vein isolation (PVI). Eight persAF patients had a non-contact array catheter deployed into the left atrium to collect up to 2048 AF electrograms (AEG) for 15 s. AEGs were band-pass filtered (3-30 Hz) followed by ventricular farfield cancellation. DF between 4-10 Hz and its respective organization index (OI) were calculated (4 s with 50% overlap) to produce 3D DF and OI maps. HDFA defined as the regions within a 0.25 Hz drop from the highest DF were determined and their centre of gravity (CG) calculated. Highest DF sites showed a higher OI at their core when compared to the periphery (0.422±0.101 vs. 0.386±0.126, p=0.02) and increased again organization at sites distant from the HDFAs. Similarly, after PVI, OI remained higher as compared to their periphery (0.372±0.026 vs. 0.332±0.036, p=0.22), but with significant lower values when compared with baseline (p<0.0001). PersAF patients showed higher organization in the HDFAs core when compared with its periphery

Unifying automated fractionated atrial electrogram classification using electroanatomical mapping systems in persistent atrial fibrillation studies

Ablation targeting complex fractionated atrial electrograms (CFAE) for treating persistent atrial fibrillation (persAF) has shown conflicting results. Differences in automated algorithms embedded in NavX (St Jude Medical) and CARTO (Biosense Webster) could influence CF AE target identification for ablation, potentially affecting ablation outcomes. To evaluate this effect, automated CFAE classification performed by NavX and CARTO on the same bipolar electrograms from 18 persAF patients undergoing ablation was compared. Using the default thresholds, NavX classified 69±5% of the electrograms as CFAEs, while CARTO detected 35±5%% (Cohen's kappa κ≈0.3, P<0.0001). Both primary and complementary metrics for each system were optimized to balance CF AE detection for both systems. Using revised thresholds found from receiver operating characteristic curves, NavX classified 45±4%, while CARTO detected 42±5% (κ≈0.5, P<0.0001). Our work takes a first step towards the optimization of CFAE detection between NavX and CARTO by providing revised thresholds to reduce differences in CF AE classification. This would facilitate direct comparisons of persAF CFAE-guided ablation outcome guided by NavX or CARTO

Systematic differences of non-invasive dominant frequency estimation compared to invasive dominant frequency estimation in atrial fibrillation

Non-invasive analysis of atrial fibrillation (AF) using body surface mapping (BSM) has gained significant interest, with attempts at interpreting atrial spectro-temporal parameters from body surface signals. As these body surface signals could be affected by properties of the torso volume conductor, this interpretation is not always straightforward. This paper highlights the volume conductor effects and influences of the algorithm parameters for identifying the dominant frequency (DF) from cardiac signals collected simultaneously on the torso and atrial surface. Bi-atrial virtual electrograms (VEGMs) and BSMs were recorded simultaneously for 5 minutes from 10 patients undergoing ablation for persistent AF. Frequency analysis was performed on 4 s segments. DF was defined as the frequency with highest power between 4-10 Hz with and without applying organization index (OI) thresholds. The volume conductor effect was assessed by analyzing the highest DF (HDF) difference of each VEGM HDF against its BSM counterpart. Significant differences in HDF values between intra-cardiac and torso signals could be observed, independent of OI threshold. This difference increases with increasing endocardial HDF (BSM-VEGM median difference from -0.13 Hz for VEGM HDF at 6.25±0.25 Hz to -4.24 Hz at 9.75±0.25 Hz), thereby confirming the theory of the volume conductor effect in real-life situations. Applying an OI threshold strongly affected the BSM HDF area size and location and atrial HDF area location. These results suggest that volume conductor and measurement algorithm effects must be considered for appropriate clinical interpretation

Investigation on recurrent high dominant frequency spatiotemporal patterns during persistent atrial fibrillation

Atrial regions hosting dominant frequency (DF) may represent potential drivers of persistent atrial fibrillation (persAF). Previous work showed that DF can exhibit cyclic behaviour. This study aims to better understand the spatiotemporal behaviours of persAF over longer time periods. 10 patients undergoing persAF ablation targeted at DF were included. Left atrial (LA) non-contact virtual electrograms (VEGMs, Ensite Array, St Jude Medical) were collected for up to 5 min pre-/post- ablation. DF was identified as the peak from 4-10 Hz, in 4 s windows (50 % overlap). High DF (HDF) map was created and automated pattern recognition algorithm was applied to look for recurring HDF spatial patterns within each patient. Recurring HDF patterns were found in all patients. Patients who changed rhythm to atrial flutter after ablation demonstrated single dominant pattern (DP) among the recorded time period, which might consistent with the higher level of regularity during flutter. Ablation regularized AF as demonstrated by increased DP recurrence after ablation. The time interval (median [IQR]) of DP recurrence for the patients still in atrial fibrillation(AF) after ablation (7 patients) decreased from 21.1 s [11.8~49.7 s] to 15.7s [6.5~18.2 s]. The proposed method quantifies the spatiotemporal regularity of HDF DPs over long time periods and may offer a more comprehensive dynamic overview of persAF behaviour and the impact of ablation

Combination of frequency and phase to characterise the spatiotemporal behaviour of cardiac waves during persistent atrial fibrillation in humans

The spatial distribution of atrial dominant frequency (DF), phase and phase singularity points (PSs) may reflect mechanisms driving and maintaining persistent atrial fibrillation (persAF). Here we developed an automatic algorithm that combines the three parameters and depicts the complex spatiotemporal patterns of fibrillation. For 9 patients undergoing left atrial persAF ablation, noncontact virtual unipolar electrograms (VEGMs) were simultaneously collected using a balloon array (Ensite Velocity, St. Jude Medical). After removal of the far field ventricular influence, we used fast Fourier transform and Hilbert transform to detect the DF and phase of each VEGM PSs are detected by finding the curl of the spatial phase gradient. DF along with phase and PSs were plotted for each window and the behaviour of the trajectory of HDF 'clouds' was observed. Our results indicate that spatial and temporal organization correlating HDF and phase exists during persAF. Generating and analysing the maps of HDF and phase may prove helpful in understanding the spatial and temporal activation dynamics during persAF

A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.

ABSTRACT: Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration: ISRCTN21615909

Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition

Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 inhibits several excitatory ligand-gated ion channels, and to improve selectivity two synthetic analogues, PhTX-343 and PhTX-12, were developed. Previous work showed a 22-fold selectivity of PhTX-12 over PhTX-343 for embryonic muscle-type nicotinic acetylcholine receptors (nAChRs) in TE671 cells. We investigated their inhibition of different neuronal nAChR subunit combinations as well as of embryonic muscle receptors expressed in Xenopus oocytes. Whole-cell currents in response to application of acetylcholine alone or co-applied with PhTX analogue were studied by using two-electrode voltage-clamp. α3β4 nAChRs were most sensitive to PhTX-343 (IC50=12 nM at −80 mV) with α4β4, α4β2, α3β2, α7 and α1β1γδ being 5, 26, 114, 422 and 992 times less sensitive. In contrast α1β1γδ was most sensitive to PhTX-12 along with α3β4 (IC50values of 100 nM) with α4β4, α4β2, α3β2 and α7 being 3, 3, 26 and 49 times less sensitive. PhTX-343 inhibition was strongly voltage-dependent for all subunit combinations except α7, whereas this was not the case for PhTX-12 for which weak voltage dependence was observed. We conclude that PhTX-343 mainly acts as an open-channel blocker of nAChRs with strong subtype selectivity